Controversy exists concerning the mechanism(s) underlying the apparent need for and tolerance of the large digoxin doses given infants and children with congestive heart failure. Because of the dissimilar clinical response to digitalis between the young and adult patient remains uncertain, pediatric patients continue to receive high doses/kg and are at risk for digitalis toxicity. Digitalis-induced inotropy and toxicity have been shown to be associated with inhibition of myocardial monovalent cation active transport in adult animals. Transmembrane active transport of Na ion and K ion is thought to be dependent on NaK-ATPase. Age-related changes in these mechanisms and their subsequent effect on the clinical response to digitalis have not been studied. This proposal has been designed to approach, in the most direct way possible, the question whether or not the unique response of newborn myocardium to digitalis is related to age-dependent changes in myocardial monovalent active transport, as reflected by the uptake of the K ion analog Rb ion. Rb ion active transport will be delineated in cardiac tissue of fetal, neonatal and mature animals. Another portion of the proposal will focus on the correlation among cardiac function, myocardial monovalent cation transport and serum and myocardial digoxin concentrations in sheep of various ages given non-toxic doses of digoxin under steady-state conditions. Finally, we will determine whether Rb ion uptake is altered by digitalis in patients of various ages utilizing cardiac tissue discarded during surgery. To reverse transport inhibition to pre-digoxin levels digoxin-specific antibody will be used in vitro, permitting each patient to be used as his/her own control. To corroborate the Rb ion uptake studies, on analysis of NaK-ATPase activity will be performed using a linked-enzyme assay. These studies will provide substantial new and useful information regarding the mechanism of action and therapeutic application of digitalis.